Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment

Oncotarget. 2017 Feb 28;8(9):14428-14442. doi: 10.18632/oncotarget.14803.

Abstract

CXCR1 and CXCR2 chemokine receptors and their ligands (CXCL1/2/3/7/8) play an important role in tumor progression. Tested to date CXCR1/2 antagonists and chemokine-targeted antibodies were reported to affect malignant cells in vitro and in animal models. Yet, redundancy of chemotactic signals and toxicity hinder further clinical development of these approaches. In this pre-clinical study we investigated the capacity of a novel small molecule dual CXCR1/2 inhibitor, Ladarixin (LDX), to attenuate progression of experimental human melanomas. Our data showed that LDX-mediated inhibition of CXCR1/2 abrogated motility and induced apoptosis in cultured cutaneous and uveal melanoma cells and xenografts independently of the molecular defects associated with the malignant phenotype. These effects were mediated by the inhibition of AKT and NF-kB signaling pathways. Moreover, systemic treatment of melanoma-bearing mice with LDX also polarized intratumoral macrophages to M1 phenotype, abrogated intratumoral de novo angiogenesis and inhibited melanoma self-renewal. Collectively, these studies outlined the pre-requisites of the successful CXCR1/2 inhibition on malignant cells and demonstrated multifactorial effects of Ladarixin on cutaneous and uveal melanomas, suggesting therapeutic utility of LDX in treatment of various melanoma types.

Keywords: CXCR1/2 inhibitor; melanoma; melanoma apoptosis; tumor growth inhibition; tumor microenvironment.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Adhesion / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Chemotaxis
  • Humans
  • Interleukin-8 / metabolism
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Nude
  • NF-kappa B
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Interleukin-8A / antagonists & inhibitors*
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • 2'-((4'-trifluoromethanesulfonyloxy)phenyl)-N-methanesulfonylpropionamide
  • Antineoplastic Agents
  • Interleukin-8
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • Sulfonamides